The budget impact of introducing mobocertinib for the postplatinum treatment of advanced non–small cell lung cancer harboring epidermal growth factor receptor exon 20 insertion mutations

BACKGROUND: Lung cancer is a leading cause of cancer morbidity and death in the United States. Non–small cell lung cancer (NSCLC) accounts for 85% of lung cancer cases, and oncogenic mutations in the gene encoding the epidermal growth factor receptor (EGFR) are among its most common genetic causes. Although NSCLC tumors harboring more common oncogenic EGFR mutations can be effectively treated with EGFR tyrosine kinase inhibitors (TKIs), those harboring EGFR exon 20 insertion mutations respond poorly to treatment with therapies approved for advanced NSCLC, including TKIs. Mobocertinib, a first-in-class potent, oral, irreversible TKI, is effective in this population. OBJECTIVE: To estimate the budget impact, for a US health plan with 10 million members, of introducing mobocertinib for the treatment of patients with locally advanced or metastatic NSCLC harboring EGFR exon 20 insertion mutations who have been previously treated with platinum-based chemotherapy. METHODS: A budget impact model was developed to compare 2 scenarios: a reference scenario in which 50% of patients received amivantamab and 50% received physician’s choice/usual care therapy and an alternative scenario in which mobocertinib replaced the physician’s choice/usual care option. The model had a 5-year time horizon in the base case. The model included epidemiologic inputs to estimate the size of the treatment-eligible population; clinical inputs to estimate treatment duration and efficacy, as well as adverse event frequency; and cost inputs for treatment acquisition and administration, management of adverse events, monitoring, and terminal care. The duration and cost of subsequent therapies were also considered. Budget impact was reported as a total cost, as per-member per-year costs, and as per-member per-month (PMPM) costs. To assess the robustness of model estimates and identify cost drivers, one-way sensitivity analyses and a range of scenario analyses were conducted. RESULTS: The model estimated an eligible treatment population of 55 patients (11 per year) over a 5-year time horizon. In the base case, the estimated budget impact of introducing mobocertinib was $5,615,808, or $0.01 PMPM. Model findings were robust to one-way sensitivity analyses and a range of sensitivity analyses; none of these analyses led to a PMPM budget impact of more than $0.06. Cost drivers included the percentage of eligible patients, the median duration of physician’s choice/usual care therapy, patient weight, and the percentage of patients who undergo molecular testing. CONCLUSIONS: The estimated budget impact of mobocertinib is low, primarily because NSCLC harboring EGFR exon 20 insertion mutations is rare.


OBJECTIVE:
To estimate the budget impact, for a US health plan with 10 million members, of introducing mobocertinib for the treatment of patients with locally advanced or metastatic NSCLC harboring EGFR exon 20 insertion mutations who have been previously treated with platinum-based chemotherapy.

METHODS:
A budget impact model was developed to compare 2 scenarios: a reference scenario in which 50% of patients received amivantamab and 50% received physician's choice/usual care therapy and an alternative scenario in which mobocertinib replaced the physician's choice/usual care option. The model had a 5-year time horizon in the base case. The model included epidemiologic inputs to estimate the size of the treatment-eligible population; clinical inputs to estimate treatment duration and efficacy, as well as adverse event frequency; and cost inputs for treatment acquisition and administration, management of adverse events, monitoring, and terminal care. The duration and cost of subsequent therapies were also considered. Budget impact was reported as a total cost, as per-member per-year costs, and as per-member per-month (PMPM) costs. To assess the robustness of model estimates and identify cost drivers, one-way sensitivity analyses and a range of scenario analyses were conducted.

RESULTS:
The model estimated an eligible treatment population of 55 patients (11 per year) over a 5-year time horizon. In the base case, the estimated budget impact of introducing mobocertinib was $5,615,808, or $0.01 PMPM. Model findings were robust to one-way sensitivity analyses and a range of sensitivity analyses; none of these analyses

Plain language summary
Mobocertinib is a new oral treatment for a rare form of lung cancer that does not respond to other treatments, after disease worsening on chemotherapy. This analysis was conducted to estimate the added costs a health plan would incur over a 5-year period if it chose to cover this therapy. The analysis found that the budget increase over 5 years of covering mobocertinib was low ($0.01 per plan member per month).

Implications for managed care pharmacy
This study demonstrates that coverage of mobocertinib, when used as a replacement for usual care in the postplatinum setting for patients with locally advanced or metastatic non-small cell lung cancer harboring epidermal growth factor receptor exon 20 insertion mutations, has a low budget impact driven by the limited size of the treatment-eligible population.
Lung cancer is a leading cause of morbidity and death in the United States, accounting for more than 235,000 cases and 131,000 deaths in 2021 alone. 1 Approximately 85% of lung cancer cases are non-small cell lung cancer (NSCLC). 2 Of the multiple histological subtypes of NSCLC, adenocarcinoma is the most common, accounting for approximately 57% of cases. 3 In recent years, the genetic basis of adenocarcinoma NSCLC has been better characterized, with mutations in the gene encoding the epidermal growth factor receptor (EGFR) tyrosine kinase being among the most common genetic causes of this disease. 4 Most oncogenic EGFR mutations occur within exons 18 to 21; several EGFR tyrosine kinase inhibitors (TKIs), including erlotinib, gefitinib, afatinib, osimertinib, and dacomitinib, are recommended in current guidelines for the treatment of the more common types of EGFR mutation-positive NSCLC. 4,5 However, some EGFR mutations in exons 18 to 21 respond poorly to EGFR TKI therapy, particularly EGFR exon 20 insertion mutations, which account for 2.1% of recurrent or metastatic adenocarcinoma NSCLC cases. 6,7 Oncogenic insertion mutations in EGFR exon 20 generally stabilize EGFR in its active conformation leading to increased activity. 8 However, this conformational change also hinders the ability of non-exon-20-insertions-directed EGFR TKIs to bind, which accounts for the poor responsiveness of tumors harboring EGFR exon 20 insertion mutations to these therapies. 5,8,9 National Comprehensive Cancer Network (NCCN) guidelines currently recommend 2 therapies approved by the US Food and Drug Administration for the management of locally advanced or metastatic NSCLC harboring EGFR exon 20 insertion mutations that have been previously treated with platinum-based chemotherapy: amivantamab, a bispecific monoclonal antibody that binds to and inhibits EGFR and MET signaling, and mobocertinib, a first-in-class potent, oral, irreversible TKI that, unlike the other EGFR TKIs, inhibits the activity of EGFR with in-frame exon 20 insertions. [10][11][12][13][14] The objective of this analysis is to estimate the 5-year total budget impact (aggregate as well as per member per year [PMPY] and per member per month [PMPM]) for a hypothetical US health plan with 10 million members of introducing mobocertinib for the treatment of patients with locally advanced or metastatic NSCLC harboring EGFR exon 20 insertion mutations who have been previously treated with platinum-based chemotherapy.

MODEL STRUCTURE
To estimate the budget impact of introducing mobocertinib for the treatment of adult patients with locally advanced or metastatic NSCLC harboring EGFR exon 20 insertion mutations who were previously treated with platinumbased chemotherapy, a budget impact model was developed in Microsoft Excel. The model was developed in accordance with guidance from the International Society of Pharmacoeconomic Outcomes and Research and from the Institute for Clinical and Economic Review. 15,16 In the model, the budget impact of mobocertinib is estimated by comparing costs between 2 scenarios: a reference scenario in which mobocertinib is not an available treatment option and an alternative scenario in which mobocertinib is available ( Figure 1). The size of the target population in the model reflects the annual population with incident, rather than prevalent, NSCLC harboring EGFR exon 20 insertion mutations, because eligible patients with prevalent NSCLC were assumed to already have initiated a new therapy following failure of platinum-based chemotherapy. The budget impact analysis was conducted from a US payer perspective with a time horizon of 5 years. Only direct medical costs, such as treatment acquisition and administration costs, pre-and postprogression monitoring costs, costs for management of adverse events (AEs) associated with the initial treatment, and terminal care costs, were included in the model.

CONCLUSIONS:
The estimated budget impact of mobocertinib is low, primarily because NSCLC harboring EGFR exon 20 insertion mutations is rare. treatment until reaching a treatment-specific maximum duration, withdrawing because of AEs or patient choice, or disease progression (although patients could remain on initial therapy following progression if they are still experiencing benefit). In the model, the time during which patients remain on initial therapy is based on treatment duration data, the time before disease progression is based on progression-free survival (PFS) data, and the time before death is based on overall survival (OS) data.

MODEL INPUTS
Clinical and cost inputs for the model are shown in Table 1. Costs are expressed as 2020 USD; costs were inflated to 2020 based on Bureau of Labor Statistics inflation data (https://www.bls.gov/data/) as appropriate.
Eligible Population. The base-case analysis, which assumes a US health plan with a covered population of 10 million, estimates that there will be 11 new patients per year eligible for treatment with mobocertinib. This estimate is based on the annual incidence of lung cancer in the United States, the percentage of lung cancer cases that are locally advanced or metastatic adenocarcinoma NSCLC harboring EGFR exon 20 insertion mutations, and the percentage of such cases 50% received physician's choice/usual care; the alternative scenario assumed that 50% of patients received amivantamab and 50% received mobocertinib (ie, in the alternative scenario, mobocertinib replaced physician's choice/usual care in the treatment mix). The market share assumptions were tested in scenario analyses. Subsequent therapies were the NCCN-recommended therapies for patients with advanced NSCLC after the second occurrence of disease progression, with market share based on normalized percentages observed for those therapies in the Flatiron database. 10,17 The model includes 6 health states, including 2 progression-free states (on initial and subsequent therapy), 3 progressed states (on initial, subsequent, and after subsequent therapy), and death. Subsequent therapy was included in the progression-free health state based on expert clinical opinion that, in aggressive indications such as NSCLC with EGFR exon 20 insertion mutations, if treatment discontinuation is for reasons other than progression, the tendency will be to put patients on another therapy as soon as possible. At each cycle, patients can remain in their current state, transition to a more advanced state, or die. Once starting a treatment, patients stay on that . The base-case analysis accounted for wastage of treatments provided in vials by rounding up the number of vials per administration up to the nearest integer but did not consider dose intensity as this information was not available for all therapies. Drug administration costs were based on the route of administration, with intravenous (IV) therapies incurring a cost per administration and oral therapies incurring a one-time cost at the start of treatment.
AE Costs. The base-case analysis included cost estimates for seven grade 3 or greater AEs (anemia, diarrhea, dyspnea, hypertension, nausea, pneumonia, and stomatitis) that occurred in 3% or more of the mobocertinib-treated pooled prior platinum population. 13 This approach was considered conservative in favor of amivantamab and physician's choice/usual care, as it ignores AEs that could have a higher occurrence for these 2 treatment options. The costs for managing these events were obtained from a 2016 report on treatment options for advanced NSCLC by the Institute of Clinical and Economic Review, except for the cost for managing hypertension, which was obtained from the literature. 26,27 Weekly AE management costs by treatment for mobocertinib and amivantamab were calculated by applying the costs per event to the observed frequencies of those events (Supplementary Tables 1 and 2, available in online article) in their respective clinical trials 13,14 ; weekly AE management costs for the physician's choice/usual care group were conservatively assumed to be $0 owing to lack of safety data from the Flatiron database.
Monitoring and Terminal Care Costs. Monthly routine monitoring costs for pre-and postprogression patients were obtained from the literature 28 ; additional details are provided in the Supplementary Materials. Patients assigned to mobocertinib also incurred an additional monthly cost for monitoring for corrected QT interval (QTC) prolongation. 11 In the base-case analysis, it was assumed that patients treated with mobocertinib would undergo a monthly electrocardiogram and a quarterly echocardiogram for monitoring for QTc prolongation. QTC prolongation monitoring costs are assumed to be $0 in patients on amivantamab or physician's choice/usual care. In the base-case analysis, the terminal care cost is a one-time charge incurred during the final week of life; this cost is based on a recent published estimate. 29

MODEL OUTPUTS
Based on the estimated number of eligible patients per year in a hypothetical health plan with a covered population of 10 million members, and the clinical inputs (treatment duration, PFS, OS, and AE frequencies) of the included therapies, that have been previously treated with platinum-based chemotherapy. 2,3,7,17,18 The base-case analysis assumes that all patients with locally advanced or metastatic adenocarcinoma NSCLC undergo molecular diagnostic testing and that the annual incidence of eligible patients remains constant throughout the 5-year time horizon.
Treatment Duration and Effectiveness. The median PFS, OS, and treatment duration for mobocertinib, amivantamab, and physician's choice/usual care were obtained or derived from data presented in study publications or study reports. 13,14,17 Owing to lack of data, the median treatment duration of amivantamab was calculated by assuming that the ratio of median treatment duration to median PFS for amivantamab was equivalent to that of mobocertinib. The treatment duration of amivantamab would not impact the results of the base-case analysis as the market share of amivantamab is 50% in the reference and alternative scenarios. The recommended treatment duration for mobocertinib and amivantamab in their prescribing information is until disease progression or unacceptable toxicity, 11,12 evaluated in scenario analyses. The median treatment duration, PFS, and OS of the physician's choice/usual care group were based on the above-mentioned analysis of the Flatiron database. 17 Median treatment durations of NCCN guidelines-recommended subsequent therapies were obtained from the literature, but these values were based on patients with relapsed or refractory NSCLC as they were not reported by treatment line.
Drug Costs. Drug acquisition costs were based on their wholesale acquisition cost from the Red Book. 24 The wholesale acquisition cost reflects the manufacturer's list price of the drug when sold to the wholesalers, and it is a better representation of actual market prices than other benchmarks (eg, wholesale price). For physician's choice/usual care, drug acquisition costs were based on a weighted average of the treatments administered in the above-mentioned Flatiron database analysis. 17

Results
The base-case model estimated an eligible treatment population of 55 patients (11 per year during the 5-year time horizon) with locally advanced or metastatic adenocarcinoma NSCLC harboring EGFR exon 20 insertion mutations who had previously received platinum-based chemotherapy in a health plan with 10 million members. In the base-case reference scenario, half of this population would receive amivantamab and half would receive physician's choice/ usual care therapy. In the alternative scenario, half of the eligible population would receive mobocertinib, half would receive amivantamab, and none would receive physician's choice/usual care. In the base case, the total 5-year budget in the reference scenario was $10,802,072, compared with $16,417,880 in the alternative scenario, for an incremental budget impact of $5,615,808 due to the replacement of the physician's choice/usual care treatment option with mobocertinib ( Table 2). Expressed in per-member cost, the 5-year budget impact of mobocertinib is estimated to be $0.56 PMPY and $0.01 PMPM. The total budget impact of mobocertinib increased gradually from $752,083 in year 1 to $1,312,708 in year 5. Over the entire time horizon, the acquisition cost for mobocertinib ($5,476,740) accounted for nearly 98% of the total budget impact estimated by the model. Monitoring and AE management costs, partly offset by lower costs for drug administration, subsequent therapy acquisition, and terminal care, accounted for the remainder of the total budget impact.
The results of the one-way sensitivity analyses are summarized in Figure 2. Key cost drivers include the percentage of patients with locally advanced or metastatic adenocarcinoma NSCLC whose tumors harbor EGFR exon 20 insertion mutations, the median treatment duration of patients who receive physician's choice/usual care therapy, patient weight, and the percentage of patients who undergo molecular testing. Two of these cost drivers (percentage of patients who harbor EGFR exon 20 insertion mutations and the percentage of patients who undergo molecular testing) are directly related to the budget impact of mobocertinib, which rises with higher input values and falls with lower input values. For the 2 other cost drivers, patient weight and median treatment duration of the physician's choice/usual care therapy, there is an inverse relationship with mobocertinib budget impact, as increased patient weight and the model estimated the budget impact of the alternative scenario compared with the reference scenario over a 5-year time horizon. The key difference between the 2 scenarios was the replacement of the reference scenario physician's choice/usual care option with mobocertinib, both administered to 50% of the eligible population. In both scenarios, the other 50% of the eligible population received amivantamab.
In accordance with ISPOR recommendations, 15 the 5-year budget impact was presented year by year as well as in total, and no discounting was used. Model outputs included total drug acquisition and administration costs for initial and subsequent therapies, AE management costs associated with the initial therapy, pre-and postprogression monitoring costs (including QTC prolongation monitoring costs), and terminal care costs. These outputs were then used to calculate the total budget, in aggregate as well as PMPY and PMPM, for the reference and alternative scenarios. The total budget impact was calculated as the difference between the alternative and reference scenarios.

SENSITIVITY ANALYSES
One-way sensitivity analyses were conducted to assess the sensitivity of the model output to changes in individual inputs and to identify key cost drivers. Parameters that were varied included epidemiologic inputs (molecular testing frequency and percentage of patients harboring EGFR exon 20 insertion mutations), patient characteristics (body weight and BSA), clinical inputs (median treatment duration, PFS, and OS for mobocertinib, amivantamab, and physician's choice/usual care; median treatment duration for subsequent therapies), and cost inputs (administration costs as well as monitoring, AE management, and terminal care costs). Parameters were either varied by assumption (±20%) or based on study reports or publications. The ranges tested for each variable are presented in Supplementary Table 3.

SCENARIO ANALYSES
To further evaluate the robustness of the model to variations of its assumptions and parameters, a series of scenarios was analyzed, including analysis of shorter time horizons (1, 2, 3, and 4 years); higher and lower market share for physician's choice/usual care in the reference scenario; 100% uptake of mobocertinib in the alternative scenario; a treatment to progression assumption instead of the previously observed duration of treatment; vial sharing (and thus no wastage); dose intensity; elimination of IV administration costs or the one-off oral treatment administration cost; different subsequent therapy treatment patterns than that assumed in the base case; higher costs for AE management for mobocertinib, postprogression monitoring, and terminal care; and an

TABLE 2
Budget Impact of Mobocertinib cancer-locally advanced or metastatic NSCLC harboring EGFR exon 20 insertion mutations-after previous treatment with platinum-based chemotherapy. 11 Prior to the introduction of mobocertinib, such patients received amivantamab or a range of additional treatment options with limited effectiveness. 12,17 The analysis assumed that, following its introduction, mobocertinib would acquire the 50% market share held by physician's choice/usual care treatment in year 1 and maintain that market share throughout the 5-year time horizon, whereas amivantamab maintained a 50% market share prior to and following the introduction of mobocertinib. Overall, the total budget impact of mobocertinib was $5,615,808 over 5 years, which is equivalent to $0.01 PMPM. Nearly 98% of the total budget impact, $5,476,740, was attributable to mobocertinib acquisition costs. The low estimated PMPM budget impact is comparable to those suggested by budget impact analyses of treatments for other rare oncogenic mutations associated with NSCLC, which varied from -$0.0029 to $0.01 PMPM during the first year following introduction (the budget impact of mobocertinib was $0.01 PMPM during the first year). [30][31][32][33][34][35][36] The estimated PMPM budget impact of mobocertinib ($0.01) was robust to a range of one-way sensitivity analyses and scenario analyses. None of the one-way sensitivity treatment duration lead to higher costs for the physician's choice/usual care therapy in the reference group. Beyond the 4 cost drivers discussed above, the budget impact model was not sensitive to other parameters evaluated by one-way sensitivity analyses.
The estimated budget impact of mobocertinib was robust to a range of scenarios examined (Table 3), none of which increased the PMPM budget impact. In particular, 100% uptake of mobocertinib in the alterative scenario, significant increases in AE management costs (10-fold), postprogression monitoring costs (up to ~13-fold), and terminal care costs (up to 4-fold) had no impact on the PMPM budget impact. Evaluation of shorter time horizons resulted in lower budget impact estimates, likely due to a reduction in the number of treated patients.

Discussion
This analysis estimated that the budget impact of adding mobocertinib to the formulary of a private US health plan with 10 million members would be low, owing principally to the fact that mobocertinib targets a small subpopulation of patients with NSCLC. Mobocertinib is indicated for the treatment of patients with a rare form of lung  costs are accrued equally in the reference and alternative scenarios given the assumption of 50% market share for amivantamab in both scenarios. This study demonstrates that coverage of mobocertinib in the postplatinum setting for patients with locally advanced or metastatic NSCLC harboring EGFR exon 20 insertion mutations has a low budget impact driven by the limited size of the treatment-eligible population. In addition, a different study demonstrated that mobocertinib provides value to patients, significantly reducing the risk of disease progression by 43% (hazard ratio = 0.57; 95% In the base-case analysis, the price of amivantamab was $2,986.43 for 1 vial of 350 mg. 24 At the time this manuscript was written, the price of a 350-mg vial of amivantamab had increased to $3,147.70 24 ; the dose of amivantamab is 1,050 mg (3 vials) for patients with a body weight of less than 80 kg and 1,400 mg (4 vials) for patients with a body weight of greater than or equal to 80 kg weekly for 4 weeks, then every 2 weeks until disease progression or unacceptable toxicity. 12 The new price of amivantamab would not change the budget impact associated with the introduction of mobocertinib. This is because the amivantamab-related

TABLE 3
Results of Scenario Analysis (continued) continued on next page retrospective analysis of the real-world Flatiron database. 17 As a result, the model assumes that absolute treatment effects are exchangeable across population, and therefore that all between-treatment differences in clinical variables can be attributed to the treatment-an assumption that cannot be verified with existing data. However, multiple one-way sensitivity analyses and scenario analyses that varied the clinical inputs did not detect a substantial impact on the overall budget impact. Moreover, because the retrospective analysis of the Flatiron database identified only 50 patients meeting the eligibility criteria for mobocertinib, and patients in this population received 17 different therapies (the most common being nivolumab, administered to 15 patients), the patient numbers were too small to generate reliable clinical inputs for all of the individual therapies administered. 17 This limitation was addressed in 2 ways: in the base case, clinical inputs from the full Flatiron database population CI = 0.36-0.90) and of death by 47% (hazard ratio = 0.53; 95% CI = 0.33-0.83) when compared with the same physician's choice/usual care from the US Flatiron database included in this budget impact analysis. 37 Similar results were reported in a second study comparing mobocertinib against a physician's choice/usual care from a real-world dataset from Germany, 38 supporting the global clinical value of mobocertinib in EGFR exon 20-mutated NSCLC.

LIMITATIONS
A limitation in the model is that, because locally advanced or metastatic NSCLC harboring EGFR exon 20 insertion mutations that has been previously treated with platinumbased chemotherapy is rare, clinical inputs from the model (treatment duration, PFS, OS, and AEs) for mobocertinib and amivantamab were obtained from open-label nonrandomized trials. 13,14 Clinical inputs for other chemotherapeutic agents used to treat this population were obtained from a for the treatment of patients with locally advanced or metastatic NSCLC harboring EGFR exon 20 insertion mutations who have been previously treated with platinum-based chemotherapy was estimated to account for 98% of the total budget impact, which is partially offset by savings in administration costs of the initial treatment due to the oral administration of mobocertinib (compared with the IV administration of amivantamab), and the acquisition and administration costs of subsequent treatments.

DISCLOSURES
Dr Hernandez is an employee of Takeda Pharmaceuticals America, Inc. Dr Young was an employee of Takeda Pharmaceuticals America, Inc., at the time this study was conducted. This study and the editorial assistance were funded by Takeda Pharmaceuticals America, Inc.
were aggregated as a "physician's choice/usual care" treatment. As an alternative, a scenario was considered in which an individualized approach was used. In this scenario, the market shares of individual treatments were based on the Flatiron database treatment patterns and the clinical inputs for each treatment were obtained from the literature (although these data were not specific to patients with EGFR exon 20 insertion mutations). Both approaches suggested a comparable budget impact. The market share assumption in the model is that mobocertinib would fully replace the physician's choice/ usual care mix of treatment in year 1 and maintain a 50% market share throughout the 5-year time horizon. At the same time, the 50% market share for amivantamab in the reference scenario is maintained throughout the 5 years following the introduction of mobocertinib. Thus, this analysis does not contemplate a slower uptake of mobocertinib, which may be reasonable given the observed effectiveness of this therapy and that of the physician's choice/usual care option. 13,17,37 However, this analysis also does not contemplate whether amivantamab or mobocertinib might increase its market share above 50% during the 5-year time horizon, except for a scenario in which mobocertinib was assumed to have 100% of the market share every year in the alternative scenario. In this scenario, the 5-year PMPM budget impact was in line with the base-case analysis ($0.01).

Conclusions
This budget impact analysis estimated that the overall budget impact of the introduction of mobocertinib is low ($0.01 PMPM over a 5-year time horizon), primarily because the indicated population is rare. The acquisition costs for mobocertinib